A number of synthetic methods for the preparation of Imiquimod are known, some of which use the corresponding 4-chloro-1H-imidazo[4,5-c]quinoline (I) as an intermediate.
One of these processes is disclosed in U.S. Pat. No. 4,689,338 and can be represented according to the following Scheme 1:

The synthetic scheme 1 involves, inter alia, the condensation of a quinoline (5), having amino groups at the 3- and 4- positions, with a trialkyl-orthoester to afford the 1H-imidazo[4,5-c]quinoline derivative (6), followed by introduction of a chlorine substituent at the 4-position, previous oxidation of the nitrogen at the 5-position and reaction of the resulting N-oxide (7) with a chlorinated agent. The chlorine atom at the 4-position is then substituted with an amino group by treatment with ammonia. It is apparent from the scheme herein reported that this process is time-consuming and complex. Moreover, the synthesis makes use of nitro derivatives (2), (3) and (4), in addition to the N-oxide (7), which are known to give uncontrollable reactions potentially hazardous to the operators.
The synthesis of Imiquimod via the corresponding 4-chloro-1H-imidazo[4,5-c]quinoline (I) is also disclosed in U.S. Pat. No. 4,988,815, according to the following Scheme 2:

The synthetic Scheme 2 requires, inter alia, the nitration of a compound (9); the introduction of two chlorine atoms at the 2 and 4 positions of a compound (10) to obtain 2,4-dichloro-3-nitroquinoline (11); the amination at the 4 position to give a compound (12); the reduction of the nitro group at the 3 position; the condensation of the quinoline (13) having amino groups at the 3 and 4 positions with a trialkyl-orthoester to afford 4-chloro-1H-imidazo[4,5-c]quinoline (I); and finally the substitution of the chlorine atom at the 4 position with an amino group to give Imiquimod. In this case also the process is time-consuming and complex, and the use of nitro derivatives (10), (11) and (12) involves the already mentioned risks. Alternative synthetic routes for the preparation of Imiquimod are reported in WO 97/48704. One of these is represented in the following Scheme 3:

The process involves the preparation of intermediate (15) which requires, inter alia, the use of nitric acid and sodium azide, products known to be dangerous. Furthermore, said intermediate, like other intermediates useful for the synthesis of Imiquimod, is characterized by the simultaneous presence of a nitro group and a tetrazole ring. These functionalities are known to give the molecule high decomposition energy, which involves risks in handling it. Moreover, these synthetic processes also are long and cumbersome.
There is therefore the need for an alternative process for the preparation of Imiquimod, which is well suited to the industrial production.
It has been found that intermediate (I), described above, can be conveniently obtained with a preparation procedure which is simpler, safer and makes use of commercially available intermediates. The advantages of the novel process for the preparation of Imiquimod, which involve no potentially hazardous intermediates, will be further evidenced in the following.